New frontiers in primary immunodeficiency disorders: immunology and beyond….

Abstract

Primary immunodeficiencies (PIDs) include more than 130 different disorders affecting the development and function of the immune system [1, 2]. PIDs are generally monogenic disorders with a Mendelian inheritance, although a more complex polygenic origin has been described in some cases. PIDs are characterized by a variable clinical spectrum. As for other genetic diseases, phenotypic diversity is often caused by disease penetrance and interactions between genetic and environmental factors. PIDs are rare and have an overall prevalence of approximately 1:10,000 live births, with the exception of IgA deficiency (IgAD). However, a much higher rate is observed among populations with high consanguinity rates or genetically isolated. PIDs are classified according to the component of the immune system that is mostly engaged. Defects in adaptive immune responses include antibody deficiency syndromes and combined immunodeficiencies (CIDs). Conversely, impairment of innate immunity comprises disorders of several cells and molecules involved in the first defense against pathogen (i.e., phagocytes, Toll-like receptors, complement, NK cell). All of these forms are characterized by increased susceptibility to recurrent infections, severe infections, and sometime distinctive susceptibility to various types of pathogens depending on the nature of the immune defect. In addition, there are some forms of PIDs presenting mainly with a phenotype of immune dysregulation rather than immunodeficiency, and there are also syndromes with complex phenotype in which immunodeficiency is only one of multiple components of the disease spectrum. PIDs affecting the B and T cell compartment are traditionally the ‘‘classic’’ forms of inherited immune deficit widely described and usually recognized also by general practitioners. Defective antibody production causes increased susceptibility, primarily to bacterial infections with involvement of the upper and lower respiratory tract (otitis, sinusitis, and pneumonia), although recurrent viral infections are also common as well as infections caused by parasites (i.e., Giardia species) [2, 3, 4]. Primary antibody deficiencies (PAD) are the largest group of inherited disorders of the immune system [5] and comprise a variety of defects that interfere with B cell development, maturation, and/or function. They are mainly characterized by a marked reduction or absence of serum immunoglobulins (Ig) due to disturbed B cell differentiation. X-linked agammaglobulinemia (XLA) is a well-described condition affecting males and characterized by mutation of the X-linked Bruton’s tyrosine kinase (BTK) gene [6, 7], named after Dr. Bruton, who described the first agammaglobulinemia patient in 1952 [8]. BTK, a transduction molecule of both pre-B cell-receptor (pre-BCR) and BCR, is essential for B cell differentiation in bone marrow. Besides XLA, many other gene defects were found as responsible of PAD and most of them have only been identified over the past 6 years. Moreover, the discovery of new PAD has contributed also to improve the clinical care of affected patients. The review by van der Burg et al. E. Gambineri (&) Department of Sciences for Woman and Child’s Health, ‘‘Anna Meyer’’ Children’s Hospital, Haematology-Oncology Department, BMT Unit, University of Florence, Viale Gaetano Pieraccini, 24, 50139 Florence, Italy e-mail: eleonora.gambineri@unifi.it Cell. Mol. Life Sci. (2012) 69:1–5 DOI 10.1007/s00018-011-0833-0 Cellular and Molecular Life Sciences